Introduction: This application has two main objectives: (1) facilitate Dr. Monica E. Calkins' continued transition to independent investigator; (2) undertake a longitudinal investigation of risk factors (endophenotypes) in youths judged at high risk of developing psychosis. Background: Schizophrenia is a severe mental disorder affecting one out of every 100 adults. Yet, genes contributing to schizophrenia risk remain elusive, rendering it impossible to develop programs for early identification and prevention of this tragic disorder. A major obstacle is that the disorder we call schizophrenia is not the best target for the gene search. Instead, we should target simpler characteristics called "endophenotypes", e.g., abilities like remembering, paying attention, and producing simple eye movements. Research with adult schizophrenia patients and their families indicates that emdophenotypes are associated with schizophrenia and tend to run in families. However, .little work has evaluated them in young people to determine whether they can help us predict, and possibly prevent, the development of schizophrenia. Growing evidence indicates that "prodromal" symptoms occurring prior to the full-blown illness are associated with a high rate of conversion to schizophrenia. The current application aims to merge endophenotype and prodromal strategies to examine the developmental course and heritability of endophenotypes in youths at-risk for psychosis. Research Project: A battery of psychophysiological and neuropsychological candidate endophenotypes will be prospectively assessed in 60 young (age 14-25) pairs of siblings. Comprehensive baseline diagnostic assessment will allow classification of probands as (a) genetic + clinical risk for schizophrenia (prodromal symptoms + immediate family member with schizophrenia; 20 pair) (b) clinical risk for schizophrenia (prodromal symptoms + no family history; 20 pair) or (c) low-risk for schizophrenia (no prodromal symptoms or family history; 20 pair). Follow-up (1 yr) will inform the developmental course of endophenotypes and relationship to prodromal symptoms. Environment: Training will occur at the University of Pennsylvania under the mentorship of Bruce Turetsky, M.D., and Raquel Gur, M.D., Ph.D. Research Career Development: Through mentored activities and formal coursework, the candidate seeks to (1) develop expertise in the design and analysis of an expanded repertoire of endophenotypes; (2) enhance her knowledge of recruitment, diagnosis and treatment of at-risk adolescents; (3) develop proficiency in longitudinal analysis of developmental data (4) enhance her knowledge of psychiatric genetic and epidemiology methods (5) prepare and submit an R01. Relevance: Detection of candidate endophenotypes in vulnerable individuals could help narrow the search for schizophrenia susceptibility genes by providing evidence that inherited characteristics associated with schizophrenia are seen prior to illness onset, and one day could be used in early identification and intervention. [unreadable] [unreadable] [unreadable] [unreadable]